PROJECT SUMMARY Atrial fibrillation (AF) is the most common heart rhythm disturbance encountered in clinical practice, affecting approximately 2.3 million people in the United States. AF is an independent risk factor for stroke, congestive heart failure and mortality. Current therapies for AF are inadequate and are associated with limited long term success rates and significant risks. Although many risk factors for AF have been identified, our understanding of the underlying pathogenic mechanisms of AF remains elusive. The public health burden of AF, combined with significant gaps in our knowledge of its pathogenesis and the lack of effective treatment, underscore the critical need for new research into its pathogenesis. A recent 2015 NHLBI document outlining strategic research priorities proposed that the identification of novel targets for drug development was a high priority of research to reduce human disease. This proposal sets out to address this priority area by identifying a unifying mechanistic explanation for the pathogenesis of AF, potentially forming the basis for designing novel targeted therapies to prevent or reverse this prevalent human disease. There is accumulating evidence to suggest that autoimmune mechanisms could be implicated in the pathogenesis of AF. Our own preliminary data suggest that autoimmune diseases as a group are more prevalent in patients with AF than non-AF controls. Therefore, the central hypothesis of this proposal is that AF is an autoimmune-mediated disease. The overall objectives of this application are to determine whether autoimmune diseases are associated with AF development and to identify specific diagnostic and prognostic biomarkers that will improve the ability to accurately predict risk of AF development. In aim 1, we will analyze epidemiologic data from Olmsted County, Minnesota to estimate the prevalence of autoimmune diseases (in aggregate) in patients with incident AF and thereby establish their association with AF. In aim 2, we will prospectively enroll patients with and without AF and determine their serum cytokine levels and assess the functional responses of T cells on the basis of cytokine production after in vitro T-cell specific stimulation, using state-of-the-art Luminex bead-based multiplex technology. The proposed work is significant because a better understanding of the interactions between autoimmune mechanisms and AF is expected to have broad translational value by 1) enhancing our ability to identify individuals at risk of AF and 2) facilitating the development of novel, targeted therapies for the management and prevention of AF. The proposed translational research is innovative because it seeks to identify a novel causative biologic pathway for the development of AF, using a multidisciplinary approach. At the completion of these aims, the role of autoimmune mechanisms in the pathogenesis of AF will be established and the cytokines profiles of individuals at risk of developing AF will be characterized. Therefore, this proposal will enable better stratification of at-risk patients, and provide a framework for advancement of translational investigations in this field to promote health and reduce the burden of cardiovascular disease.